- SLE is a multifactorial, heterogeneous disease, characterized by aberrant immune regulation, but the genetic traits conferring susceptibility and their interaction with environmental factors have not been elucidated yet. The long-term objectives of this proposal are to identify the factors predisposing to SLE. IL-6, a member of the cytokine network that regulates immune responses, is aberrantly expressed in SLE. Alleles of an AT-rich minisatellite in the IL-6 3' flanking region are associated with Caucasian and African-American SLE and with accumulation and stability of IL-6 mRNA. Thus, 3' alleles may affect IL-6 expression, and contribute to SLE pathogenesis. The aims of this application are: (1) To confirm with higher level of significance the correlation of SLE-associated 3' alleles with upregulated IL-6, and to determine whether the SLE-associated 3' alleles constitute a basic trait that could delineate, along with other SLE factors, specific subsets of SLE; (2) to identify the molecular event(s) in IL-6 upregulation that are affected by the 3' alleles and the 3' sequences having gene regulatory potential; (3) to evaluate the possible association of IL-6 promoter alleles with SLE and differential IL-6 biology and, (4) to identify the DNA allelic sequences that contribute to IL-6 gene deregulation in SLE, and their possible interactions with other factors by measuring mRNA levels and stability of transfectants of CAT constructs containing allelic 3' flanking sequences identified for gene-regulatory potential by EMSA and DNase footprinting. Study of interactions of the 3' flanking allelic sequences with the IL-6 3' UTR, with cytokines affecting IL-6 mRNA stability in SLE (i.e., TNFalpha and IL-10), and with IL-6 promoter or 5' UT sequences. These studies can elucidate the pathways leading to deregulated IL-6 production in SLE and, by identifying the relevant DNA sequences, can provide useful predictive tools and advance our search for targeted therapy.